Elucidating the chromatin-dependent mechanisms governing chronic inflammatory activation of endothelial cells in atherosclerosis.
阐明控制动脉粥样硬化中内皮细胞慢性炎症激活的染色质依赖性机制。
基本信息
- 批准号:10586037
- 负责人:
- 金额:$ 58.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAnimalsAnti-Inflammatory AgentsAortaArchitectureAtherosclerosisAutomobile DrivingBasal CellBiological AssayBlood VesselsCardiovascular DiseasesCellsChromatinChromatin StructureChronicCoupledCytokine ActivationDataDiseaseEndothelial CellsEngineeringEnhancersFunctional disorderGene ExpressionGenesGeneticGenetic TranscriptionGoalsGrowthHealthHistonesHumanInflammationInflammatoryInflammatory ResponseKnock-outLaboratoriesLeukocytesLipidsMapsMediatorMedical ResearchMissionModelingMolecularMorbidity - disease rateMusNational Heart, Lung, and Blood InstituteNodalOutcomePathologicPathologyPathway interactionsPatientsPeritonitisProteinsPublic HealthPublishingRNA Polymerase IIReporterResearchResidual stateRisk FactorsRoleSeminalSignal TransductionStimulusTestingUnited StatesUnited States National Institutes of HealthVascular Endothelial CellWorkatherogenesisatherosclerosis riskburden of illnesscardiovascular disorder riskchromatin remodelingdesigndisabilitygene regulatory networkgenome-wideimprovedin vivoinnovationinsightloss of functionmortalitynew therapeutic targetnovelnovel therapeutic interventionrecruitresponsestandard of caretranscription factor
项目摘要
Project Summary and Abstract
Despite standard of care, atherosclerotic cardiovascular disease (CVD) remains a leading cause of morbidity
and mortality in the United States. In nearly half of patients, risk of CVD is elevated despite adequate control of
standard risk factors. In this group, inflammation is proposed as a key driver. Despite this insight, no targeted
anti-inflammatory therapies exist for CVD. Thus, an urgent unmet need exists to elucidate novel mechanisms of
chronic inflammation in athersclerosis. The long-term goal of my laboratory is to understand how enhancer
plasticity drives atherosclerosis through effects on gene expression that change cell state. The overall objectives
of this proposal are to 1) to elucidate how inflammatory activation of vascular endothelial cells (ECs) alters EC
identity and 2) to define the role of BRD4 in EC activation in atherogenesis. Our central hypothesis is that
prolonged inflammatory activation by cytokines and proatherogenic lipids directs a durable remodeling of
enhancers such that basal cell state is lost and a new inflammatory cell state is activated. Our hypothesis is
formulated on the basis of our previously published work as well as new preliminary data that reveal the following:
i) chronic inflammatory stimulation of human aortic ECs (HAECs) results in dynamic activation of a subset of
new super enhancers; ii) in HAECs, these new enhancer regions persist despite removing the proinflammatory
stimulus; iii) a core transcription factor (TF) circuitry can be inferred from sequence-specific TF motifs that are
enriched at chronic inflammatory super enhancers; iv) BRD4 inhibition blocks leukocyte recruitment in peritonitis
and atherogenesis in part through EC effects. The rationale for this project is that a deeper understanding of the
molecular mediators of chronic inflammation holds the promise of identifying new drug targets designed to
reverse the long-term, pathologic activation of vascular cells that drives atherosclerosis. To achieve our overall
objectives, we will pursue the following integrated, but non-interdependent specific aims: 1) To determine how
chronic, proatherogenic stimuli remodel chromatin structure and unveil new enhancers in human arterial ECs
and 2) To determine the functional role of Brd4 in maintaining EC state during atherogenesis in vivo. The overall
contribution of this work will be to elucidate how chronic inflammatory signaling establishes a new endothelial
cell state through persistent enhancer activation. The central innovation of this proposal is a conceptual shift in
research paradigm by demonstrating inflammation drives pathologic cell states in atherosclerosis by a dynamic
interplay between chromatin structure, enhancer function and gene expression.
项目摘要及摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
JONATHAN David BROWN其他文献
JONATHAN David BROWN的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('JONATHAN David BROWN', 18)}}的其他基金
Gene Therapy in Hutchinson-Gilford Progeria Syndrome
哈钦森-吉尔福德早衰综合症的基因治疗
- 批准号:
10343225 - 财政年份:2022
- 资助金额:
$ 58.64万 - 项目类别:
Gene Therapy in Hutchinson-Gilford Progeria Syndrome
哈钦森-吉尔福德早衰综合症的基因治疗
- 批准号:
10583487 - 财政年份:2022
- 资助金额:
$ 58.64万 - 项目类别:
Elucidating the chromatin-dependent mechanisms governing chronic inflammatory activation of endothelial cells in atherosclerosis.
阐明控制动脉粥样硬化中内皮细胞慢性炎症激活的染色质依赖性机制。
- 批准号:
9974212 - 财政年份:2020
- 资助金额:
$ 58.64万 - 项目类别:
Elucidating the chromatin-dependent mechanisms governing chronic inflammatory activation of endothelial cells in atherosclerosis.
阐明控制动脉粥样硬化中内皮细胞慢性炎症激活的染色质依赖性机制。
- 批准号:
10363671 - 财政年份:2020
- 资助金额:
$ 58.64万 - 项目类别:
Hepatic Lipase, PPAR-delta and Fatty Acid Metabolism
肝脂肪酶、PPAR-δ 和脂肪酸代谢
- 批准号:
8197786 - 财政年份:2010
- 资助金额:
$ 58.64万 - 项目类别:
Hepatic Lipase, PPAR-delta and Fatty Acid Metabolism
肝脂肪酶、PPAR-δ 和脂肪酸代谢
- 批准号:
8029238 - 财政年份:2010
- 资助金额:
$ 58.64万 - 项目类别:
Hepatic Lipase, PPAR-delta and Fatty Acid Metabolism
肝脂肪酶、PPAR-δ 和脂肪酸代谢
- 批准号:
9275086 - 财政年份:2010
- 资助金额:
$ 58.64万 - 项目类别:
Hepatic Lipase, PPAR-delta and Fatty Acid Metabolism
肝脂肪酶、PPAR-δ 和脂肪酸代谢
- 批准号:
8586546 - 财政年份:2010
- 资助金额:
$ 58.64万 - 项目类别:
Hepatic Lipase, PPAR-delta and Fatty Acid Metabolism
肝脂肪酶、PPAR-δ 和脂肪酸代谢
- 批准号:
9121837 - 财政年份:2010
- 资助金额:
$ 58.64万 - 项目类别:
Hepatic Lipase, PPAR-delta and Fatty Acid Metabolism
肝脂肪酶、PPAR-δ 和脂肪酸代谢
- 批准号:
8774840 - 财政年份:2010
- 资助金额:
$ 58.64万 - 项目类别:
相似海外基金
The earliest exploration of land by animals: from trace fossils to numerical analyses
动物对陆地的最早探索:从痕迹化石到数值分析
- 批准号:
EP/Z000920/1 - 财政年份:2025
- 资助金额:
$ 58.64万 - 项目类别:
Fellowship
Animals and geopolitics in South Asian borderlands
南亚边境地区的动物和地缘政治
- 批准号:
FT230100276 - 财政年份:2024
- 资助金额:
$ 58.64万 - 项目类别:
ARC Future Fellowships
The function of the RNA methylome in animals
RNA甲基化组在动物中的功能
- 批准号:
MR/X024261/1 - 财政年份:2024
- 资助金额:
$ 58.64万 - 项目类别:
Fellowship
Ecological and phylogenomic insights into infectious diseases in animals
对动物传染病的生态学和系统发育学见解
- 批准号:
DE240100388 - 财政年份:2024
- 资助金额:
$ 58.64万 - 项目类别:
Discovery Early Career Researcher Award
Zootropolis: Multi-species archaeological, ecological and historical approaches to animals in Medieval urban Scotland
Zootropolis:苏格兰中世纪城市动物的多物种考古、生态和历史方法
- 批准号:
2889694 - 财政年份:2023
- 资助金额:
$ 58.64万 - 项目类别:
Studentship
Using novel modelling approaches to investigate the evolution of symmetry in early animals.
使用新颖的建模方法来研究早期动物的对称性进化。
- 批准号:
2842926 - 财政年份:2023
- 资助金额:
$ 58.64万 - 项目类别:
Studentship
Study of human late fetal lung tissue and 3D in vitro organoids to replace and reduce animals in lung developmental research
研究人类晚期胎儿肺组织和 3D 体外类器官在肺发育研究中替代和减少动物
- 批准号:
NC/X001644/1 - 财政年份:2023
- 资助金额:
$ 58.64万 - 项目类别:
Training Grant
RUI: Unilateral Lasing in Underwater Animals
RUI:水下动物的单侧激光攻击
- 批准号:
2337595 - 财政年份:2023
- 资助金额:
$ 58.64万 - 项目类别:
Continuing Grant
RUI:OSIB:The effects of high disease risk on uninfected animals
RUI:OSIB:高疾病风险对未感染动物的影响
- 批准号:
2232190 - 财政年份:2023
- 资助金额:
$ 58.64万 - 项目类别:
Continuing Grant
A method for identifying taxonomy of plants and animals in metagenomic samples
一种识别宏基因组样本中植物和动物分类的方法
- 批准号:
23K17514 - 财政年份:2023
- 资助金额:
$ 58.64万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)